Low-dose Drug Research Articles

A228 RISANKIZUMAB - DRUG INDUCED LIVER INJURY; A CASE REPORT

Abstract Background Risankizumab is a humanized monoclonal antibody to IL-23. It was initially used in the treatment of plaque psoriasis with recent approval to extend use to treat moderate to severe Crohn’s disease with evidence of endoscopic healing and clinical remission of disease. In the drugs safety manual, it has been reported to have transient liver enzyme elevation that is asymptomatic and not to a degree requiring drug discontinuation. No reported data on steatohepatitis. In this article we describe a 28 year old female, who had no evidence of liver disease in the past who underwent treatment with Risankizumab and within several months developed evidence of steatohepatitis with radiological evidence of significant hepatomegaly. Aims Case report details Drug induced liver injury to Risankizumab. Methods Case Report Results Drug induced liver injury with elevated liver enzyme levels and liver biopsy showing drug related liver changes likely in the setting of Risankizumab use. Conclusions Risankizumab is a newly approved drug in the setting of Crohn's disease, although described in the drug assessment report that it may cause transient hepatitis or eleveted liver enzymes in the setting of lower drug dose for Psoriasis use, the higher drug level used in the setting of Crohn's disease has not been formally evaluated and no previous known case reports of Drug induced Liver Injury to Risankizumab causing severe steatohepatitis Funding Agencies None

Mitigating non-genetic resistance to checkpoint inhibition based on multiple states of immune exhaustion

Despite the revolutionary impact of immune checkpoint inhibition on cancer therapy, the lack of response in a subset of patients, as well as the emergence of resistance, remain significant challenges. Here we explore the theoretical consequences of the existence of multiple states of immune cell exhaustion on response to checkpoint inhibition therapy. In particular, we consider the emerging understanding that T cells can exist in various states: fully functioning cytotoxic cells, reversibly exhausted cells with minimal cytotoxicity, and terminally exhausted cells. We hypothesize that inflammation augmented by drug activity triggers transitions between these phenotypes, which can lead to non-genetic resistance to checkpoint inhibitors. We introduce a conceptual mathematical model, coupled with a standard 2-compartment pharmacometric (PK) model, that incorporates these mechanisms. Simulations of the model reveal that, within this framework, the emergence of resistance to checkpoint inhibitors can be mitigated through altering the dose and the frequency of administration. Our analysis also reveals that standard PK metrics do not correlate with treatment outcome. However, we do find that levels of inflammation that we assume trigger the transition from the reversibly to terminally exhausted states play a critical role in therapeutic outcome. A simulation of a population that has different values of this transition threshold reveals that while the standard high-dose, low-frequency dosing strategy can be an effective therapeutic design for some, it is likely to fail a significant fraction of the population. Conversely, a metronomic-like strategy that distributes a fixed amount of drug over many doses given close together is predicted to be effective across the entire simulated population, even at a relatively low cumulative drug dose. We also demonstrate that these predictions hold if the transitions between different states of immune cell exhaustion are triggered by prolonged antigen exposure, an alternative mechanism that has been implicated in this process. Our theoretical analyses demonstrate the potential of mitigating resistance to checkpoint inhibitors via dose modulation.

The clinical and neuroimaging differences between vascular parkinsonism and Parkinson's disease: a case-control study.

Parkinson's disease (PD) and vascular parkinsonism (VaP) have highly overlapping phenotypes, and different prognosis. This study comprehensively investigated the clinical, brain MRI and transcranial sonography differences between VaP and PD. Forty-eight patients with PD, 27 patients with VaP, and 29 healthy controls were compared. All patients were assessed using the MDS-UPDRS, Berg Balance Scale (BBS), Ten-Meter Walking Test (10-MWT), Time Up and Go Test, and Non-Motor Symptoms Scale. Beck Depression Inventory, PD questionnaire- 39, international urine incontinence scale, cognitive assessment scales, MRI brain and transcranial colour-coded doppler. The study was registered on clinical-Trial.gov (NCT04308135) on 03/12/2020. VaP patients showed significantly older age of onset, shorter disease duration, lower drug doses and levodopa responsiveness, higher On and Off axial scores, On and Off BBS, higher On scores for PIGD, rigidity, bradykinesia and total motor MDS-UPDRS, lower On and Off tremor, lower-half predominance, lower asymmetrical presentation and symmetric index than PD patients. VaP patients had worse non-motor symptoms Scale (NMSS) than controls except for perceptual problems/hallucinations but better symptoms than PD patients except for urinary dysfunction. Quality of life (QoL) was impaired in VaP patients and was correlated with motor function and NMSs. The VaP group had significantly higher white matter lesions and brain atrophy, with lower hyperechogenicity of the substantia nigra and more impaired cerebral vascular resistance and vasoreactivity than the PD group. VaP has a characteristic motor and non-motor profile, with impaired QoL, white matter, and transcranial sonography abnormalities that differentiate it from PD. Further studies are warranted to explore the role of vascular lesions in the pathogenesis of VaP. The registered identifier NCT04308135 on clinical-Trial.gov. Registered on 03/12/2020.

Formulation and Evaluation of Phenylephrine Nasal Gels

The primary objective of this study is to develop and evaluate phenylephrine nasal gels, aiming for stable blood levels with lower drug doses through consistent administration, avoiding first-pass hepatic metabolism. Compatibility among the drug, polymers, and lipids was confirmed using FTIR and DSC spectra. Phenylephrine nasal gels were formulated, and their clarity assessed. The gels (ONGF1-ONGF8) had pH values of 6.1-7.2, spreadability of 18.33-21.62 g/cm/sec, and viscosity of 934.2-966.2 centipoises. Drug concentration in these formulations varied from 85.52% to 98.88%, indicating acceptable medication content. Gel strength ranged from 64% to 95%. In-vitro drug release of phenylephrine showed 77% to 95% diffusion for ONGF1. The release kinetics followed first order, zero order, Higuchi model, and Korsemeyer-Peppas equations. Kinetic values for all formulations were tabulated. ONGF1 exhibited the most efficient release, with 95% of the drug released within 7 hours, demonstrating a diffusion mechanism followed by non-Fickian transport, adhering to both zero order and Korsemeyer-Peppas models.Top of Form

New Molecular Complexes of Glycyrrhizic Acid Monoammonium Salt (Glycyram) with Fluoroquinolone Antibiotics

Aims: The study aimed to search of new molecular complexes of licorice saponin with fluoroquinolone antibiotics and to explore their pharmaceutical potential. Background: Molecular complexation of triterpene glycosides with pharmaceutical substances reduces side effects and therapeutic doses, increases bioavailability and stability, and expands the spectrum of biological activity of drugs. Glycyrrhizic acid is the major triterpene glycoside of licorice. Molecular complexes of monoammonium salt of glycyrrhizic acid (glycyram, GC) with fluoroquinolone antibiotics have not been described. Objectives: This study is devoted to the preparation and analysis of molecular complexes of GC with fluoroquinolones, and investigation of their antimicrobial activity. Methods: Complexation was studied via FT-IR spectroscopy, UV-Vis spectroscopy and mass spectrometry methods. Results: Molecular complexes of GC with fluoroquinolone antibiotics, along with their benzylated derivatives, were obtained for the first time. Conclusion: The complexes composition was defined as 1:1. Intermolecular hydrogen bonds are formed during complexation. In addition, stability constants of 105 М-1 order were calculated. Some complexes are comparable in antimicrobial activity with individual antibiotics ciprofloxacin (CP) and moxifloxacin (Moc) or surpass them in relation to a number of bacteria. These molecular complexes could be potential low-dose drugs with antimicrobial activity.

Low skeletal muscle radiodensity is a risk factor for adjuvant chemotherapy discontinuation in colorectal cancer.

Previously, we reported SMR (skeletal muscle radiodensity) as a potential prognostic marker for colorectal cancer. However, there have been limited studies on the association between SMR and the continuation of adjuvant chemotherapy in colorectal cancer. In this retrospective study, 143 colorectal cancer patients underwent curative surgery and adjuvant chemotherapy using the CAPOX regimen. Patients' SMRs were measured from preoperative CT images and divided into low (bottom quarter) and high (top three quarters) SMR groups. We compared chemotherapy cycles, capecitabine and oxaliplatin doses, and adverse effects in each group. The low SMR group had significantly fewer patients completing adjuvant chemotherapy compared to the high SMR group (44% vs. 68%, P < 0.01). Capecitabine and oxaliplatin doses were also lower in the low SMR group. Incidences of Grade 2 or Grade 3 adverse effects did not differ between groups, but treatment discontinuation due to adverse effects was significantly higher in the low SMR group. Logistic regression analysis revealed Stage III disease (odds ratio 18.09, 95% CI 1.41-231.55) and low SMR (odds ratio 3.26, 95% CI 1.11-9.56) as factors associated with unsuccessful treatment completion. Additionally, a higher proportion of low SMR patients received fewer than 2 cycles of chemotherapy (50% vs. 12%). The low SMR group showed higher treatment incompletion rates and received lower drug doses during adjuvant chemotherapy. Low SMR independently contributed to treatment non-completion in colorectal cancer patients.

Gastroprotective Chitosan Nanoparticles Loaded with Oleuropein: An In Vivo Proof of Concept.

Oleuropein is the main constituent of olive leaf extract, and it has shown antioxidant and gastroprotective properties against gastric ulcers. Chitosan nanoparticles are known for their mucoadhesive abilities, and consequently, they can increase the retention time of drugs in the gastrointestinal tract. Therefore, loading oleuropein onto chitosan nanoparticles is expected to enhance its biological efficiency. Oleuropein-loaded chitosan nanoparticles were prepared and characterized for particle size, surface charge, in vitro release, and anti-inflammatory activity. Their in vivo efficacy was assessed by measuring specific inflammatory and protective biomarkers, along with histopathological examination. The optimum oleuropein chitosan nanoparticles were cationic, had a size of 174.3 ± 2.4 nm and an entrapment efficiency of 92.81%, and released 70% of oleuropein within 8 h. They recorded a lower IC50 in comparison to oleuropein solutions for membrane stabilization of RBCs (22.6 vs. 25.6 µg/mL) and lipoxygenase inhibition (7.17 vs. 15.6 µg/mL). In an ethanol-induced gastric ulcer in vivo model, they decreased IL-1β, TNF-α, and TBARS levels by 2.1, 1.7, and 1.3 fold, respectively, in comparison to increments caused by exposure to ethanol. Moreover, they increased prostaglandin E2 and catalase enzyme levels by 2.4 and 3.8 fold, respectively. Immunohistochemical examination showed that oleuropein chitosan nanoparticles markedly lowered the expression of IL-6 and caspase-3 in gastric tissues in comparison to oleuropein solution. Overall, oleuropein chitosan nanoparticles showed superior gastroprotective effects to oleuropein solution since comparable effects were demonstrated at a 12-fold lower drug dose, delineating that chitosan nanoparticles indeed enhanced the potency of oleuropein as a gastroprotective agent.

Research progress in brain-targeted nasal drug delivery.

The unique anatomical and physiological connections between the nasal cavity and brain provide a pathway for bypassing the blood-brain barrier to allow for direct brain-targeted drug delivery through nasal administration. There are several advantages of nasal administration compared with other routes; for example, the first-pass effect that leads to the metabolism of orally administered drugs can be bypassed, and the poor compliance associated with injections can be minimized. Nasal administration can also help maximize brain-targeted drug delivery, allowing for high pharmacological activity at lower drug dosages, thereby minimizing the likelihood of adverse effects and providing a highly promising drug delivery pathway for the treatment of central nervous system diseases. The aim of this review article was to briefly describe the physiological structures of the nasal cavity and brain, the pathways through which drugs can enter the brain through the nose, the factors affecting brain-targeted nasal drug delivery, methods to improve brain-targeted nasal drug delivery systems through the application of related biomaterials, common experimental methods used in intranasal drug delivery research, and the current limitations of such approaches, providing a solid foundation for further in-depth research on intranasal brain-targeted drug delivery systems (see Graphical Abstract).

Initial treatment with a single capsule containing half-dose quadruple therapy versus standard-dose dual therapy in hypertensive patients (QUADUAL): statistical analysis plan for a randomized, blinded, crossover trial

BackgroundCombined antihypertensive therapy has obvious advantages over single drug therapy. Hypertension guidelines fully affirm the efficacy of dual combination in initial antihypertensive therapy. Recent studies have also pointed out that the quadruple combination of very low-dose antihypertensive drugs is superior to single drugs. However, whether low-dose quadruple therapy is better than dual combination is unknown.Methods/designA randomized double-blind crossover clinical trial will be conducted to compare the efficacy and safety of low-dose quadruple antihypertensives (irbesartan 75 mg + metoprolol 23.75 mg + amlodipine 2.5 mg + indapamide 1.25 mg) with standard-dose dual antihypertensives (irbesartan 150 mg + amlodipine 5 mg) in the initial treatment of patients with mild to moderate hypertension (140–179/90–109 mmHg). Ninety patients are required and will be recruited and randomly assigned in a 1:1 ratio to two crossover groups. Two groups will receive a different combination therapy for 4 weeks, then switch to the other combination therapy for 4 weeks, with a 2-week wash-out. Antihypertensive effects and related adverse effects of the two antihypertensive combination treatments will be compared. The primary outcome, i.e., mean 24-h systolic blood pressure in ambulatory blood pressure monitoring, will be assessed via linear mixed-effects model.DiscussionThis statistical analysis plan will be confirmed prior to blind review and data lock before un-blinding and is sought to increase the validity of the QUADUAL trial.Trial registrationClinicalTrials.gov, NCT05377203. Registered May 11, 2022, https://clinicaltrials.gov/study/NCT05377203.

A glycosylated AIE-active Fe(III) photosensitizer activated by the tumor microenvironment for synergistic type I photodynamic and chemodynamic therapy.

Photodynamic therapy (PDT) and chemodynamic therapy (CDT) are both promising cancer treatments to inhibit tumor cells by generating highly cytotoxic reactive oxygen species (ROS). Herein, we report a novel tumor microenvironment (TME) stimulus-responsive water-soluble glycosylated photosensitizer (BT-TPE@Fe-Lac), which can serve as a high-efficiency antitumor agent by combining PDT and CDT, based on the coordination of Fe3+ with lactosyl bis(2-pyridylmethyl)amine and an AIE luminogen (benzothiazole-hydroxytetraphenylethene, BT-TPE). BT-TPE@Fe-Lac is stable under physiological conditions and selectively targets HepG2 cells via asialoglycoprotein receptor (ASGPR)-mediated endocytosis. It rapidly dissociates into AIE-active BT-TPE molecules and a lactosyl ferric(III) complex in the acidic lysosomes of cancer cells. Upon exposure to light, BT-TPE produces O2˙- radicals for type I PDT. The ferric(III) complex is reduced to an Fe(II) complex upon depletion of glutathione, which primes the breakdown of endogenous H2O2 within the tumor microenvironment, thus generating highly toxic ˙OH for enhanced CDT. Compared with the monotherapy of PDT or CDT, BT-TPE@Fe-Lac can significantly increase the intracellular ROS levels to induce more tumor cell death under low drug doses and hypoxia-dependent conditions. This strategy leverages the unique properties of the TME to optimize therapeutic outcomes, offering a promising approach for the TME-responsive nanoplatform in advanced cancer therapy.

Advancements in rheumatoid arthritis therapy: a journey from conventional therapy to precision medicine via nanoparticles targeting immune cells.

Rheumatoid arthritis (RA) is a progressive autoimmune disease that mainly affects the inner lining of the synovial joints and leads to chronic inflammation. While RA is not known as lethal, recent research indicates that it may be a silent killer because of its strong association with an increased risk of chronic lung and heart diseases. Patients develop these systemic consequences due to the regular uptake of heavy drugs such as disease-modifying antirheumatic medications (DMARDs), glucocorticoids (GCs), nonsteroidal anti-inflammatory medicines (NSAIDs), etc. Nevertheless, a number of these medications have off-target effects, which might cause adverse toxicity, and have started to become resistant in patients as well. Therefore, alternative and promising therapeutic techniques must be explored and adopted, such as post-translational modification inhibitors (like protein arginine deiminase inhibitors), RNA interference by siRNA, epigenetic drugs, peptide therapy, etc., specifically in macrophages, neutrophils, Treg cells and dendritic cells (DCs). As the target cells are specific, ensuring targeted delivery is also equally important, which can be achieved with the advent of nanotechnology. Furthermore, these nanocarriers have fewer off-site side effects, enable drug combinations, and allow for lower drug dosages. Among the nanoparticles that can be used for targeting, there are both inorganic and organic nanomaterials such as solid-lipid nanoparticles, liposomes, hydrogels, dendrimers, and biomimetics that have been discussed. This review highlights contemporary therapy options targeting macrophages, neutrophils, Treg cells, and DCs and explores the application of diverse nanotechnological techniques to enhance precision RA therapies.

Phosphoproteomics guides low dose drug combination of cisplatin and silmitasertib against concurrent chemoradiation resistant cervical cancer

Cisplatin based concurrent chemoradiotherapy (CCRT) is the standard treatment for cervical patients with locally advanced disease. Despite the improved survival rates and prognosis observed in patients undergoing CCRT, over 30–40%...

Synergistic D-Amino Acids Based Antimicrobial Cocktails Formulated via High-Throughput Screening and Machine Learning.

Antimicrobial resistance (AMR) from pathogenic bacterial biofilms has become a global health issue while developing novel antimicrobials is inefficient and costly. Combining existing multiple drugs with enhanced efficacy and/or reduced toxicity may be a promising approach to treat AMR. D-amino acids mixtures coupled with antibiotics can provide new therapies for drug-resistance infection with reduced toxicity by lower drug dosage requirements. However, iterative trial-and-error experiments are not tenable to prioritize credible drug formulations, owing to the extremely large number of possible combinations. Herein, a new avenue is provide to accelerate the exploration of desirable antimicrobial formulations via high-throughput screening and machine learning optimization. Such an intelligent method can navigate the large search space and rapidly identify the D-amino acid mixtures with the highest anti-biofilm efficiency and also the synergisms between D-amino acid mixtures and antibiotics. The optimized drug cocktails exhibit high antimicrobial efficacy while remaining non-toxic, which is demonstrated not only from in vitro assessments but also the first in vivo study using a lung infection mouse model.

Hybrid Nanoparticle-Assisted Chemo-Photothermal Therapy and Photoacoustic Imaging in a Three-Dimensional Breast Cancer Cell Model.

Bioinspired nanoparticles have recently been gaining attention as promising multifunctional nanoplatforms for therapeutic applications in cancer, including breast cancer. Here, the efficiency of the chemo-photothermal and photoacoustic properties of hybrid albumin-modified nanoparticles (HSA-NPs) loaded with doxorubicin was evaluated in a three-dimensional breast cancer cell model. The HSA-NPs showed a higher uptake and deeper penetration into breast cancer spheroids than healthy breast cell 3D cultures. Confocal microscopy revealed that, in tumour spheroids incubated with doxorubicin-loaded NPs for 16 h, doxorubicin was mainly localised in the cytoplasm, while a strong signal was detectable at the nuclear level after 24 h, suggesting a time-dependent uptake. To evaluate the cytotoxicity of doxorubicin-loaded NPs, tumour spheroids were treated for up to 96 h with increasing concentrations of NPs, showing marked toxicity only at the highest concentration of doxorubicin. When doxorubicin administration was combined with laser photothermal irradiation, enhanced cytotoxicity was observed at lower concentrations and incubation times. Finally, the photoacoustic properties of doxorubicin-loaded NPs were evaluated in tumour spheroids, showing a detectable signal increasing with NP concentration. Overall, our data show that the combined effect of chemo-photothermal therapy results in a shorter exposure time to doxorubicin and a lower drug dose. Furthermore, owing to the photoacoustic properties of the NPs, this nanoplatform may represent a good candidate for theranostic applications.

Anesthetic Drugs as a Pharmacologic Stress Test for the Aging Brain: Towards a Real Time EEG Read‐Out

AbstractBackgroundRoughly 65 million older adults (ie age &gt;65 years) undergo anesthesia/surgery each year and are at risk for postoperative delirium. Further, postoperative delirium is itself associated with increased long term risk for Alzheimer’s Disease and Related Dementias (ADRD). Recent work has also shown that some patients have deeply suppressed neurophysiologic (ie EEG) patterns in response to relatively low anesthetic drug doses, and that these patients are more likely to have preoperative cognitive impairment and to develop postoperative delirium. However, to date few if any studies have examined the role of specific ADRD pathologic processes and neuroimaging abnormalities in these altered anesthetic dose‐dependent EEG response patterns in older adults.MethodWe examined relationships between intraoperative 32 channel EEG data (in cognitively normal older non‐cardiac surgery patients who received inhaled anesthetics such as isoflurane) and both 1) preoperative CSF ADRD biomarker levels and 2) preoperative structural and functional MRI imaging characteristics. CSF abeta, tau and p‐tau‐181p were measured using the Roche elecsys platform. Frontal‐parietal alpha band phase lag index and alpha power were calculated from frontal and parietal electrode regions of interest (ROIs), and normalized to inhaled anesthetic dosage.ResultLower anesthetic dose‐adjusted frontal‐parietal alpha band phase lag index values were associated with higher preoperative CSF p‐tau/Ab ratios (p = 0.013, N = 9‐18 per group, Fig 1A), lower cortical thickness in the left and right parahippocampal regions (Fig 1B, N = 16, p&lt;0.001), and altered resting state fMRI connectivity between the left anterior entorhinal cortex and both the left medial prefrontal cortex and the left angular gyrus (two key default mode network regions; Fig 1C, N = 16, peak voxel p&lt;0.01).ConclusionThese data suggest that both molecular markers and neuroimaging features of preclinical AD neuropathology in cognitively normal older adults are associated with altered anesthetic dose‐dependent changes in neurophysiologic/EEG functional connectivity. More generally, these data demonstrate the need for additional studies to understand the extent to which intraoperative EEG data can be used to make inferences about ADRD‐related neuropathologic processes in older adults, which could provide a real‐time EEG “readout” for the stress test of anesthesia and surgery on the aging brain

Nano-controlled release of phytohormones will broaden its application on plant protection

Phytohormone is a key regulator of plant growth and development. It has important effects on plant under biotic and abiotic stresses. However, the dose control of phytohormone is always a difficult problem in the application process, which limits the application range of phytohormone. Nanotechnology, because of its characteristics of controlled release, targeted therapy, non-pollution, high adsorption, lower volatilization of active substances, and low dosage of drug, comes into researchers’ vision. Nanomaterials were directly applicated on crops at the early stage, and then active substances, such as pesticides, were encapsulated with nanomaterials, also achieved good results in the field. Currently, more and more attentions have been paid to nano-enabled delivery of phytohormones to plants, and formed a new field in agriculture. In present work, we reviewed the existing literatures, focused on the important regulatory roles of phytohormones in plant growth and development and their application potential, and the development and application prospect of nanomaterials combined with phytohormones were also have been discussed.

Renal Allograft Function Outcomes After Conversion from Conventional Immunosuppression to Belatacept Plus Low-Dose Conventional Drug Regimen

Renal Allograft Function Outcomes After Conversion from Conventional Immunosuppression to Belatacept Plus Low-Dose Conventional Drug Regimen

Drug-detecting bioelectronic nose based on odor cue memory combined with a brain computer interface

The international drug situation is increasingly, various new drugs are hidden in public places through changing forms and packaging, which brings new challenges to drug enforcement. This study proposes a drug-detecting bioelectronic nose based on odor cue memory combined with brain-computer interface and optogenetic regulation technologies. First, the rats were trained to generate positive memories of drug odors through food reward training, and multichannel microelectrodes were implanted into the DG region of the hippocampus for responsible memory retrieval, the spike signals of individual neurons and the local field potential signals of population neurons in the brain region were collected for pattern recognition and analysis. Preliminary experimental results have shown that when low-dose drugs are buried in a hidden area, rats can find the location of the drugs in a very short time, and when close to the relevant area, there is a significant change in the energy value and time-frequency spectrum signal coupling of the returned data, which can be extracted to indicate that the rats have found the drugs. Second, we labled the neuronal activity marker c-fos and revealed more robust activation in the DG region following odor detection. We modulated these neurons through neuroregulatory technology, so that the rats could recognize drugs by retrieving memories more quickly. We conceive that the drug-detecting rat robot can detect trace amounts of various drugs in complex terrain and multiple scenes, which is of great significance for anti-drug work in the future.

Levothyroxine poisoning in children – should we really be afraid?

Aim: L-thyroxine intoxication is rarely seen in children; however, it can be worrying for clinicians and parents. This study aimed to present the clinical and laboratory findings of children admitted to the pediatric emergency department with l-thyroxine intoxication.&#x0D; &#x0D; Methods: Patients admitted to the pediatric emergency department with l-thyroxine intake between January 2015 and June 2022 were included in this retrospective study. The patient’s clinical characteristics, laboratory findings, treatment, and hospital costs were recorded and analyzed.&#x0D; &#x0D; Results: This study included 33 pediatric patients with thyroxine intoxication. The median age was 35 months (The interquartile range (IQR) 25-47.5) and 19 of them were girls (57,5%). No patient had a clinical symptom at the admittance. One patient had massive l-thyroxine intake and two patients had tachycardia. Gastric lavage and activated charcoal were used in 18 patients. Four patients were followed in the pediatric intensive care unit and one of them was treated with propranolol. The median time of hospital stay was 24 hours (IQR 13,5-84). The median cost of the treatment was $73 (IQR56.2-116.75).&#x0D; &#x0D; Conclusion: L-thyroxine intoxication usually occurs with low drug doses in children and has a benign prognosis. Routine hospitalization of these patients, particularly with low drug dose intake, should be questioned considering the treatment cost.

Quantification of Drospirenone- and Ethinyl Estradiol-Related Impurities in a Combined Pharmaceutical Dosage Form by a Chromatography Method With a QbD Robustness Study.

The estimation of drugs containing drospirenone (DRSP) and ethinyl estradiol (EE), and their related impurities, in low-dose oral contraceptive drug products is an extremely challenging target. The proposed research sought to develop and validate a stability-indicating method for quantifying drug substances and their related impurities in tablet formulation. To develop and validate a simple, specific, accurate, precise, and stability-indicating reverse-phase (RP)-HPLC method for quantification of DRSP, EE, and their impurities in accordance with International Conference on Harmonisation (ICH) guidelines. The separation was achieved using an Agilent Zorbax SB C18 column (4.6 mm × 250 mm, 5 µm) with a detection wavelength of 215 nm and mobile phases A (100% acetonitrile) and B (acetonitrile-water, 1 + 3, v/v) at a flow rate of 1.3 mL/min and a column temperature of 40°C. The recovery study of each impurity was conducted in the range of 24 to 72 µg/mL for DRSP-related impurities and 0.2 to 0.6 µg/mL for EE-related impurities with respect to the specification limit. A linearity study was conducted over a range of 1.5 to 90 µg/mL for DRSP and DRSP-related impurities, and 0.125 to 0.75 µg/mL for EE-related impurities. A Quality by Design (QbD) study demonstrated the method's robustness. As per current guidelines, a stability-indicating method has been developed for the determination of impurities in DRSP/EE film-coated tablets. A QbD-based robustness test was performed and the method was found to be robust. An accurate, precise, stability-indicating, gradient RP-HPLC method has been developed and validated to determine DRSP, EE, and nine related impurities in tablet formulation. A QbD technique was used to establish a robustness study.